RU2020132725A - MICRO-RNA AND OBESITY - Google Patents

MICRO-RNA AND OBESITY Download PDF

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RU2020132725A
RU2020132725A RU2020132725A RU2020132725A RU2020132725A RU 2020132725 A RU2020132725 A RU 2020132725A RU 2020132725 A RU2020132725 A RU 2020132725A RU 2020132725 A RU2020132725 A RU 2020132725A RU 2020132725 A RU2020132725 A RU 2020132725A
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oligonucleotide
inhibitor
based inhibitor
protein
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RU2020132725A
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Пьер Пауло ПАНДОЛЬФИ
Риккардо ПАНЕЛЛА
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Бет Израэль Диконесс Медикал Сентр
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    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/06—Antihyperlipidemics
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    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2310/11—Antisense
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
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    • C12N2310/141—MicroRNAs, miRNAs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/323—Chemical structure of the sugar modified ring structure
    • C12N2310/3231—Chemical structure of the sugar modified ring structure having an additional ring, e.g. LNA, ENA
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
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    • C12N2320/00—Applications; Uses
    • C12N2320/50—Methods for regulating/modulating their activity

Claims (34)

1. Способ лечения или профилактики метаболического расстройства, включающий введение эффективного количества ингибитора miR-22 нуждающемуся в этом субъекту.1. A method of treating or preventing a metabolic disorder, comprising administering an effective amount of a miR-22 inhibitor to a subject in need thereof. 2. Способ по п. 1, отличающийся тем, что экспрессия и/или активность miR-22 снижается у субъекта после введения ингибитора.2. The method of claim. 1, characterized in that the expression and/or activity of miR-22 is reduced in the subject after administration of the inhibitor. 3. Способ по п. 1 или 2, отличающийся тем, что ингибитор miR-22 представляет собой ингибитор на основе олигонуклеотидов.3. The method according to claim 1 or 2, wherein the miR-22 inhibitor is an oligonucleotide-based inhibitor. 4. Способ по п. 3, отличающийся тем, что ингибитор на основе олигонуклеотидов содержит последовательность, которая по меньшей мере на около 75%, около 80%, около 85%, около 90%, около 95%, около 96%, около 97%, около 98%, около 99% или около 100% комплементарна зрелой последовательности miR-22.4. The method of claim 3, wherein the oligonucleotide-based inhibitor comprises a sequence that is at least about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97 %, about 98%, about 99%, or about 100% complementary to the mature miR-22 sequence. 5. Способ по п. 3 или 4, отличающийся тем, что ингибитор на основе олигонуклеотидов включает дезоксинуклеотиды или рибонуклеотиды.5. The method according to claim 3 or 4, wherein the oligonucleotide-based inhibitor comprises deoxynucleotides or ribonucleotides. 6. Способ по любому из пп. 3-5, отличающийся тем, что ингибитор на основе олигонуклеотидов является одноцепочечным.6. The method according to any one of paragraphs. 3-5, characterized in that the oligonucleotide-based inhibitor is single-stranded. 7. Способ по любому из пп. 3-5, отличающийся тем, что ингибитор на основе олигонуклеотидов является двухцепочечным.7. The method according to any one of paragraphs. 3-5, characterized in that the oligonucleotide-based inhibitor is double-stranded. 8. Способ по любому из пп. 3-7, отличающийся тем, что ингибитор на основе олигонуклеотидов содержит один или более химически модифицированных нуклеотидов.8. The method according to any one of paragraphs. 3-7, characterized in that the oligonucleotide-based inhibitor contains one or more chemically modified nucleotides. 9. Способ по п. 8, отличающийся тем, что химически модифицированные нуклеотиды представляют собой закрытые нуклеотиды (LNA).9. The method according to claim 8, characterized in that the chemically modified nucleotides are closed nucleotides (LNA). 10. Способ по любому из пп. 3-9, отличающийся тем, что ингибитор на основе олигонуклеотидов содержит около 25, около 20, около 15, около 10, около 9, около 8, около 7, около 6 или около 5 или менее нуклеотидов.10. The method according to any one of paragraphs. 3-9, characterized in that the oligonucleotide-based inhibitor contains about 25, about 20, about 15, about 10, about 9, about 8, about 7, about 6, or about 5 or less nucleotides. 11. Способ по любому из пп. 3-10, отличающийся тем, что ингибитор на основе олигонуклеотидов конъюгирован с одним или более фрагментами N-ацетилгалактозамина (GalNAc).11. The method according to any one of paragraphs. 3-10, characterized in that the oligonucleotide-based inhibitor is conjugated to one or more N-acetylgalactosamine (GalNAc) moieties. 12. Способ по любому из пп. 3-11, отличающийся тем, что ингибитор на основе олигонуклеотидов представляет собой ингибитор на основе антисмыслового олигонуклеотида.12. The method according to any one of paragraphs. 3-11, wherein the oligonucleotide-based inhibitor is an antisense oligonucleotide-based inhibitor. 13. Способ по любому из пп. 3-11, отличающийся тем, что ингибитор на основе олигонуклеотидов представляет собой малую интерферирующую РНК (миРНК).13. The method according to any one of paragraphs. 3-11, characterized in that the oligonucleotide-based inhibitor is a small interfering RNA (miRNA). 14. Способ по любому из пп. 3-11, отличающийся тем, что ингибитор на основе олигонуклеотидов представляет собой аптамер.14. The method according to any one of paragraphs. 3-11, characterized in that the oligonucleotide-based inhibitor is an aptamer. 15. Способ по п. 1 или 2, отличающийся тем, что ингибитор miR-22 представляет собой ингибитор на основе пептида или белка.15. The method according to claim 1 or 2, wherein the miR-22 inhibitor is a peptide or protein based inhibitor. 16. Способ по п. 15, отличающийся тем, что ингибитор на основе белка представляет собой антитело или его антигенсвязывающую часть.16. The method of claim 15 wherein the protein-based inhibitor is an antibody or an antigen-binding portion thereof. 17. Способ по п. 1 или 2, отличающийся тем, что ингибитор miR-22 представляет собой ингибитор на основе малой молекулы.17. The method of claim 1 or 2, wherein the miR-22 inhibitor is a small molecule inhibitor. 18. Способ по любому из предшествующих пунктов, отличающийся тем, что расстройство обмена веществ представляет собой ожирение.18. The method according to any one of the preceding claims, characterized in that the metabolic disorder is obesity. 19. Способ по п. 18, отличающийся тем, что субъект страдает синдромом Прадера-Вилли.19. The method of claim 18, wherein the subject suffers from Prader-Willi syndrome. 20. Способ по п. 18, отличающийся тем, что субъект страдает гиперхолестеринемией.20. The method of claim 18, wherein the subject suffers from hypercholesterolemia. 21. Способ по п. 18, отличающийся тем, что субъект имеет вариант белка, связанного с жировой массой и ожирением (FTO), и/или демонстрирует повышенную регуляцию экспрессии и/или активности FTO.21. The method according to claim 18, wherein the subject has a protein variant associated with fat mass and obesity (FTO) and/or shows upregulation of FTO expression and/or activity. 22. Способ по любому из пп. 18-21, отличающийся тем, что субъект страдает ожирением и имеет индекс массы тела более около 30.22. The method according to any one of paragraphs. 18-21, wherein the subject is obese and has a body mass index greater than about 30. 23. Способ по любому из пп. 18-21, отличающийся тем, что субъект имеет избыточную массу тела и индекс массы тела около 25-29,9.23. The method according to any one of paragraphs. 18-21, characterized in that the subject is overweight and has a body mass index of about 25-29.9. 24. Способ по любому из пп. 18-23, отличающийся тем, что способ вызывает потерю массы тела.24. The method according to any one of paragraphs. 18-23, characterized in that the method causes weight loss. 25. Способ по п. 24, отличающийся тем, что способ вызывает общую потерю массы тела у субъекта около 1%, около 5%, около 10%, около 15%, около 20% или около 25% или более.25. The method of claim 24, wherein the method causes an overall weight loss in the subject of about 1%, about 5%, about 10%, about 15%, about 20%, or about 25% or more. 26. Способ по любому из пп. 18-23, отличающийся тем, что способ предотвращает увеличение массы тела.26. The method according to any one of paragraphs. 18-23, characterized in that the method prevents weight gain. 27. Способ по любому из пп. 18-26, отличающийся тем, что способ уменьшает или предотвращает рост жировой ткани.27. The method according to any one of paragraphs. 18-26, characterized in that the method reduces or prevents the growth of adipose tissue. 28. Способ по любому из пп. 18-26, отличающийся тем, что способ ухудшает дифференцировку адипоцитов.28. The method according to any one of paragraphs. 18-26, characterized in that the method impairs the differentiation of adipocytes. 29. Способ по любому из предшествующих пунктов, отличающийся тем, что расстройство обмена веществ представляет собой жировую болезнь печени.29. The method according to any one of the preceding claims, wherein the metabolic disorder is fatty liver disease. 30. Способ по п. 29, отличающийся тем, что жировая болезнь печени выбрана из неалкогольной жировой болезни печени (НАЖБП) или неалкогольного стеатогепатита (НАСГ).30. The method of claim 29 wherein the fatty liver disease is selected from non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). 31. Способ по п. 29 или 30, отличающийся тем, что способ снижает или предотвращает стеатоз печени.31. The method according to claim 29 or 30, characterized in that the method reduces or prevents hepatic steatosis. 32. Способ по любому из пп. 29-31, отличающийся тем, что способ уменьшает или предотвращает фиброз печени.32. The method according to any one of paragraphs. 29-31, characterized in that the method reduces or prevents liver fibrosis. 33. Способ по любому из пп. 1-32, отличающийся тем, что способ снижает активность и/или экспрессию варианта белка, связанного с жировой массой и ожирением (FTO), ALKB гомолога 5 (ALKBH5), белка, связывающего CCAAT/энхансер - альфа (CEBPα), гамма-рецептора, активируемого пролифератором пероксисом (PPARγ), альфа-рецептора, активируемого пролифератором пероксисом (PPARa), АТФ цитратлиазы (ACLY), PPARγ со-активатора-α (PGC1-α), специфического белка 1 (SP1), фактора роста фибробластов 21 (FGF-21), разобщающего белка 1 (UCP1), транскрипта 4 с включенным повреждением ДНК (DDIT-4, REDD1), опухолевого белка p63 (TP63), фактора роста фибробластов 1 (FGF1) и/или белка, подобного метилтрансферазе 3 (METTL3).33. The method according to any one of paragraphs. 1-32, characterized in that the method reduces the activity and/or expression of a protein variant associated with fat mass and obesity (FTO), ALKB homologue 5 (ALKBH5), CCAAT/enhancer-alpha binding protein (CEBPα), gamma receptor , peroxisome proliferator-activated receptor (PPARγ), peroxisome proliferator-activated receptor alpha (PPARa), citrate lyase ATP (ACLY), PPARγ co-activator-α (PGC1-α), specific protein 1 (SP1), fibroblast growth factor 21 (FGF -21), uncoupling protein 1 (UCP1), DNA damage-included transcript 4 (DDIT-4, REDD1), p63 tumor protein (TP63), fibroblast growth factor 1 (FGF1), and/or methyltransferase-like protein 3 (METTL3) . 34. Способ по любому из пп. 1-33, отличающийся тем, что способ повышает активность и/или экспрессию гомолога фосфатазы и тензина (PTEN), и/или tet метилцитозин диоксигеназы 2 (TET2).34. The method according to any one of paragraphs. 1-33, characterized in that the method increases the activity and/or expression of the homologue of phosphatase and tensin (PTEN), and/or tet methylcytosine dioxygenase 2 (TET2).
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